The overall goal of this study is to examine determinants of nicotine reinforcement thresholds in rats in order to provide a scientific basis for evaluation of low-nicotine tobacco products. Such products are being introduced by industry as alternatives to higher nicotine products or examined clinically as aids to smoking cessation. In addition, gradual reduction of the levels of nicotine in cigarettes to render them non-addictive has been proposed as a population-wide regulatory approach to promoting smoking cessation and preventing initiation of smoking in adolescents. However, the feasibility and consequences of reducing nicotine in tobacco products is largely unknown. Key questions include: a) What is the threshold level of nicotine needed to maintain smoking in adults, and would reducing nicotine delivery below this threshold be sufficient to also prevent development of nicotine addiction in adolescents? b) To what extent would compensatory smoking, an adverse side effect, occur in response to progressively reduced nicotine cigarettes? c) What behavioral and pharmacological factors contribute to individual variability in nicotine reinforcement thresholds and compensation that represent potential sources of individual variability in addiction and health risk across different populations? d) Would smoking cessation medications facilitate or impede smoking cessation in the context of nicotine regulation? Because experimental analysis of initiation of smoking in adolescents, and control of nicotine exposure in general, is difficult to accomplish in human studies, animal research is needed to examine comprehensively these issues. Behavioral economic (i.e., demand curve) analysis is uniquely suited to the present studies and will be used to provide information on determinants of the reinforcing efficacy of nicotine that will complement analysis of nicotine reinforcement thresholds. The primary hypothesis to be tested is that the nicotine reinforcement threshold and elasticity of demand (an index of reinforcing efficacy) for maintenance of nicotine self-administration (NSA) in adult rats during reductions in unit dose is lower than that for acquisition of NSA in adolescents. Specific Aim 1 will characterize nicotine reinforcement thresholds, elasticity of demand, and degree of compensation during maintenance of NSA in adult rats, and examine whether these variables are correlated with individual differences in baseline intake, measures of extinction, and nicotine metabolism. Specific Aim 2 will characterize and compare nicotine reinforcement thresholds and elasticity of demand for acquisition of NSA in adolescent and adult rats, and examine whether these variables are correlated with individual differences in nicotine metabolism. Specific Aim 3 will test the hypothesis that currently-approved (nicotine replacement, varenicline) and novel (immunization) medications for cessation will increase the nicotine reinforcement threshold and elasticity of demand for nicotine, and reduce compensation. This project will provide an extensive assessment of the effects of nicotine unit dose manipulation on NSA and could have important clinical, public health, and policy implications for nicotine reduction products and strategies. PUBLIC HEALTH RELEVANCE: Tobacco products with reduced nicotine content are being marketed by industry and also being considered as a population-wide regulatory approach to promote cessation and prevent initiation of smoking in adolescents. However, the feasibility, efficacy, and safety of this approach has not been firmly established due to a lack of scientific data. Findings from the present project will provide scientific data on the effects of nicotine dose reduction in an animal model of smoking, identify potential biological or pharmacologic contributors to individual differences that might influence the applicability of nicotine dose reduction, identify potential adverse consequences, and clarify the role of smoking cessation medications in this context. As such, the present study could contribute to the scientific basis for evaluation of reduced nicotine tobacco products and their clinical and public health consequences.